Indiana University-Purdue University Indianapolis (IUPUI) / Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a
wide spectrum of biological processes including apoptosis, immune response
and inflammation. S1P receptor (S1PR) ligands have been utilized as an
effective immunosuppressant, treatment in multiple sclerosis and studied as a
treatment for pain. The primary cellular response to S1P is thought to be elicited
through S1PR type 1 (S1PR1). My first goal was to understand how S1PR1
signaling affects neuronal excitability in the central amygdala (CeA), a
supraspinal node of the descending pain pathway. The CeA is made up of a
heterogenous population of neurons which form complex local and long-range
circuits. The central lateral amygdala (CeL) consists of two major populations of
inhibitory neurons identified by expression of the peptides somatostatin (Sst) and
protein kinase Cδ (PKCδ). Sst neurons have been shown to maintain control
over local circuits within the CeL and play a critical role in pain modulation. I
utilized transgenic breeding strategies to fluorescently label Sst-expressing CeL
neurons for whole-cell electrophysiology in acute brain slice. This strategy
allowed me to study the effects of S1PR1 agonist SEW2871 and S1PR1
antagonist NIBR on the cellular physiology of CeL Sst neurons. My findings
reveal intrinsically distinct subtypes of CeL Sst neurons that are uniquely affected
by S1PR1 activation, which may have implications for how S1P alters supraspinal
pain pathways.
My second goal was to assess the physiology of motor cortex neurons in
mice exposed to prenatal methadone. Methadone is a synthetic μ-opioid agonist
used for opioid maintenance therapy and chronic pain management. Methadone
treatment for opioid use disorder in pregnant women can result in structural
changes within the brain of their offspring causing and developmental delays to
their children, including poorer motor performance. Using a mouse model of
prenatal methadone exposure (PME), whole-cell electrophysiology, and analyses
of cellular morphology, I elucidated the effects of PME on primary motor cortex
(M1) output layer 5 (L5) neurons, which encompass the major cortical output
pathway for motor control. My findings provide the first evidence that PME
disrupts neuronal firing, subthreshold properties, and strength of local inputs onto
M1 L5 neurons in prepubescent mice. / 2023-05-05
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/25993 |
| Date | 04 1900 |
| Creators | Mork, Briana E. |
| Contributors | Atwood, Brady K., Sheets, Patrick L., Cummins, Theodore R., Fehrenbacher, Jill C., McKinzie, David L. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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